Single ascending oral dose pharmacokinetics and pharmacodynamics study of EV-077: the specific inhibitor of prostanoid- and isoprostane-induced cellular activation.

Abstract

PURPOSE:

This study was performed to determine the oral pharmacokinetics (PK) of EV-077 and its effects on pharmacodynamic (PD) markers. EV-077 blocks prostanoid-induced and isoprostane-induced cellular activation, and is in development for the treatment of vascular inflammation and associated complications of type-2 diabetes..

METHODS:

This single-ascending-dose mono-centre study was randomised, placebo-controlled, and double-blinded within each dose group. Seven EV-077 doses were administered sequentially as an oral solution: 0.0125, 0.125, 0.375, 0.75, 1.25, 1.875 and 2.5 mg/kg body weight. PK, platelet aggregation, bleeding time and safety parameters were measured. Seven to eight healthy male subjects were dosed per group: five to six subjects received EV-077 and two subjects received placebo.

RESULTS:

Tmax was reached rapidly between 0.5 h and 1.0 h. Both Cmax and AUC increased linearly with the dose. The apparent terminal half-life (t½z) increased with the dose, most likely reflecting the increasing last quantifiable concentration with increasing dose; at 2.5 mg/kg, it was 2.7-6.9 h. Measurement of platelet aggregation showed no effect at 0.0125 mg/kg, and a full and reversible inhibition at doses of 0.125-2.5 mg/kg. The average bleeding time was dose-dependently prolonged, but was always below 9 min. The PK/PD profile showed that at plasma concentrations above 20 ng/ml, EV-077 platelet aggregation was completely inhibited (>90 %). All tested doses were well tolerated.

CONCLUSIONS:

Orally administered EV-077 was well tolerated, readily absorbed, reached Cmax within 1 h, with a linear PK based on Cmax and AUC. The inhibition of platelet aggregation was complete and reversible at doses of 0.125 mg/kg and higher, and average bleeding time was below 9 min.

• Authors: A Richardson, K S Sakariassen, J-P Meyer, P Alberts, A S Sorensen
• Journal: European journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 69 Issue 3 Pg. 459-65 (Mar 2013) ISSN: 1432-1041 [Electronic] Germany
• PMID: 22815050 (Publication Type: Journal Article, Randomized Controlled Trial)

Chemical References

• Enzyme Inhibitors
• Platelet Aggregation Inhibitors
• Receptors, Thromboxane
• Thromboxane-A Synthase

Topics

• Administration, Oral
• Adult
• Area Under Curve
• Bleeding Time
• Dose-Response Relationship, Drug
• Double-Blind Method
• Enzyme Inhibitors (administration & dosage, adverse effects, blood, pharmacokinetics)
• Half-Life
• Humans
• Linear Models
• Male
• Metabolic Clearance Rate
• Middle Aged
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (administration & dosage, adverse effects, blood, pharmacokinetics)
• Receptors, Thromboxane (antagonists & inhibitors)
• Thromboxane-A Synthase (antagonists & inhibitors)
• Young Adult